With aging, the skeleton decreases In mass and Increases In fragility and susceptibility to fracture and it is not clear why exercise becomes less effective with aging. The osteocyte is not only a mechanosensory cell that responds to mechanical load, but also a source of factors that regulate osteoclasts and osteoblasts and act as endocrine cells to regulate other organs. Like osteocytes, muscle is also a source of signaling factors, tenned 'myokines'. Therefore, we hypothesize that active muscle not only loads the bone, but also sends soluble signals that have beneficial synergistic effects on bone cells, especially osteocytes. Our exciting data show that conditioned media (CM) from differentiated C2C12 myotubes protects osteocytes from the apoptotic effects of glucocorticoid. Interestingly, CM from differentiated myotubes had a more potent anti- apoptotic effect than CM from undifferentiated myoblasts. We have also found that myotube CM enhances osteocyte responses to shear stress, including prostaglandin production, t>-catenin translocation to the nucleus, and Akt phosphorylation. These results were confirmed using CM from isolated whole muscle explants of soleus and extensor digitomm longus muscle from 5 month old mice, which had similar protective anti-apoptotic effects on osteocytes. In striking contrast, muscle explant CM from aged 22 month old mice actually induced osteocyte cell death. Our overall hypothesis is that muscle can signal bone cells independent of the effect of loading on the skeleton and during aging, positive muscle signaling declines or converts to negative signals contributing to the aging-related decline in bone cell function. The following specific aims are proposed: To determine the effects of muscle soluble Actors on osteocyte viability and function and to determine how aging affects the ability of muscle cells to regulate osteocyte function. The completion of these specific aims will significantly advance the field of musculoskeletal biology. Identification of osteocyte viability factors produced by young muscle and of osteocyte apoptotic factors produced by aged muscle is novel and paradigm shifting. Characterizing these muscle signaling factors and their effects on bone cells should lead to novel therapeutics for treatment of both bone and muscle loss with age.